Oncogenic osteomalacia (OOM), X linked hypophosphatemic rickets (XLH) and autosomal dominant hypophosphatemic rickets (ADHR) are phenotypically similar disorders characterized by hypophosphatemia, decreased renal phosphate reabsorption, defective calcitriol synthesis, and defective skeletal mineralization. OOM is caused by mesenchymal tumors that elaborate a phosphaturic factor. XLH results from mutations in the PHEX gene, that encodes an endopeptidase. ADHR is associated with mutations of the gene encoding FGF-23. In work initiated in my K08 award, I compared gene expression profiles (SAGE) of mesenchymal tumors derived from patients with OOM and found that FGF-23 was highly-expressed. Moreover, I demonstrated that FGF-23 inhibited phosphate transport in a model of proximal renal tubular epithelia. I further demonstrated that FGF-23 is a PHEX substrate and that FGF-23 R179Q (ADHR mutation), was not cleaved by PHEX. Taken together, these findings support the hypothesis that in normal physiologic states, FGF-23 is regulated via PHEX-dependent proteolysis. However, when PHEX is inactive, FGF-23 is resistant to cleavage or FGF-23 is ectopically produced, FGF-23 accumulates and thus leads to phosphaturia. The objective of the proposed studies is to understand the role of FGF-23 in normal phosphate homeostasis and to elucidate the molecular link between FGF-23 and reduced phosphate reabsorption. First, I propose to define the normal diurnal variation of FGF-23 in humans and to measure serum FGF-23 in subjects with disorders of phosphate homeostasis. Second, I will determine if exposure to FGF-23 alters the type 2a sodium-phosphate transporter (Npt-2) transcription, protein expression or endocytic retreival from the membrane in proximal renal tubular cell lines. In mice, I will explore the effect of FGF-23 infusion on Npt-2 mRNA and protein expression and renal brush border membrane phosphate transport. Elucidating the molecular mechanism by which FGF-23 causes renal phosphate wasting will contribute substantially to our understanding of the role of FGF-23 in phosphate homeostasis.